2-Ethyl and 2-ethylidene-19-nor-vitamin D compounds

ABSTRACT

Biologically active 19-nor vitamin D analogs substituted at C-2 in the A-ring with an ethylidene or an ethyl group. These compounds have preferential activity on mobilizing calcium from bone and either high or normal intestinal calcium transport activity which allows their in vivo administration for the treatment of metabolic bone diseases where bone loss is a major concern. These compounds are also characterized by high cell differentiation activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is based on and claims priority from provisional patentapplication Ser. No. 60/208,199 filed on May 31, 2000.

BACKGROUND OF THE INVENTION

This invention relates to vitamin D compounds, and more particularly tovitamin D derivatives substituted at the carbon 2 position.

The natural hormone, 1α,25-dihydroxyvitamin D₃ and its analog inergosterol series, i.e. 1α,25-dihydroxyvitamin D₂ are known to be highlypotent regulators of calcium homeostasis in animals and humans, and morerecently their activity in cellular differentiation has beenestablished, Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987).Many structural analogs of these metabolites have been prepared andtested, including 1α-hydroxyvitamin D₃, 1α-hydroxyvitamin D₂, variousside chain homologated vitamins and fluorinated analogs. Some of thesecompounds exhibit an interesting separation of activities in celldifferentiation and calcium regulation. This difference in activity maybe useful in the treatment of a variety of diseases.

Recently, a new class of vitamin D analogs has been discovered, i.e. theso called 19-nor-vitamin D compounds, which are characterized by thereplacement of the A-ring exocyclic methylene group (carbon 19), typicalof the vitamin D system, by two hydrogen atoms. Biological testing ofsuch 19-nor-analogs (e.g., 1α,25-dihydroxy-19-nor-vitamin D₃) revealed aselective activity profile with high potency in inducing cellulardifferentiation, and very low calcium mobilizing activity. Thus, thesecompounds are potentially useful as therapeutic agents for the treatmentof malignancies, or the treatment of various skin disorders. Twodifferent methods of synthesis of such 19-nor-vitamin D analogs havebeen described (Perlmnan et al., Tetrahedron Lett. 31, 1823 (1990);Perlman et al., Tetrahedron Lett. 32, 7663 (1991), and DeLuca et al.,U.S. Pat. No. 5,086,191).

In U.S. Pat. No. 4,666,634, 2β-hydroxy and alkoxy (e.g., ED-71) analogsof 1α,25-dihydroxyvitamin D₃ have been described and examined by Chugaigroup as potential drugs for osteoporosis and as antitumor agents. Seealso Okano et al., Biochem. Biophys. Res. Commun. 163, 1444 (1989).Other 2-substituted (with hydroxyalkyl, e.g., ED-120, and fluoroalkylgroups) A-ring analogs of 1α,25-dihydroxyvitamin D₃ have also beenprepared and tested (Miyamoto et al., Chem. Pharm. Bull. 41, 1111(1993); Nishii et al., Osteoporosis Int. Suppl. 1, 190 (1993); Posner etal., J. Org. Chem. 59, 7855 (1994), and J. Org. Chem. 60, 4617 (1995)).

Recently, 2-substituted analogs of 1α,25-dihydroxy-19-norvitamin D₃ havealso been synthesized, i.e. compounds substituted at 2-position withhydroxy or alkoxy groups (DeLuca et al., U.S. Pat. No. 5,536,713), whichexhibit interesting and selective activity profiles. All these studiesindicate that binding sites in vitamin D receptors can accommodatedifferent substituents at C-2 in the synthesized vitamin D analogs.

SUMMARY OF THE INVENTION

The discovery of the hormonally active form of vitamin D₃, 1α,25-dihydroxyvitamin D₃ (1α,25-(OH)₂D₃, calcitriol, 1; FIG. 1), hasgreatly stimulated research into its physiology and chemistry. Aspreviously noted, it has been established that 1 not only regulates themineral metabolism in animals and humans, but also exerts potent effectsupon cell proliferation and cellular differentiation. Therefore, thechemistry of vitamin D has been recently focused on-the design andsynthesis of analogs that can exert selective biological actions.

In a previous investigation of the structure-activity relationship ofthe vitamin D molecule, an analog of the natural hormone 1,1α,25-dihydroxy-2-methylene-19-norvitamin D₃ (2), was prepared in whichthe exocyclic methylene group is transposed, in comparison with 1, fromC-10 to C-2. Also, 2α-methyl analog 3 was obtained by selectivehydrogenation of 2. Both analogs were characterized by significantbiological potency, enhanced especially in their isomers in the20S-series.

In a continuing search for biologically active vitamin D compounds novel19-nor analogs of 1, substituted at C-2 with ethylidene (4a,b and 5a,b)and ethyl (6a,b and 7a,b) groups, have now been synthesized and tested.Structurally the novel 2-ethylidene analogs belong to a class of 19-norvitamin D compounds characterized by the general formula I shown below:

where Y₁ and Y₂, which may be the same or different, are each selectedfrom the group consisting of hydrogen and a hydroxy-protecting group,and where the group R represents any of the typical side chains knownfor vitamin D type compounds.

Structurally the novel 2-ethyl analogs belong to a class of 19-norvitamin D compounds characterized by the general formula II shown below:

where Y₁ and Y₂, which may be the same or different, are each selectedfrom the group consisting of hydrogen and a hydroxy-protecting group,and where the group R represents any of the typical side chains knownfor vitamin D type compounds.

More specifically R can represent a saturated or unsaturated hydrocarbonradical of 1 to 35 carbons, that may be straight-chain, branched orcyclic and that may contain one or more additional substituents, such ashydroxy- or protected-hydroxy groups, fluoro, carbonyl, ester, epoxy,amino or other heteroatomic groups. Preferred side chains of this typeare represented by the structure below:

where the stereochemical center (corresponding to C-20 in steroidnumbering) may have the R or S configuration, (i.e. either the naturalconfiguration about carbon 20 or the 20-epi configuration), and where Zis selected from Y, —OY, —CH₂OY, —C≡CY, —QH═CHY, and —CH₂CH₂CH═CR³R⁴,where the double bond may have the cis or trans geometry, and where Y isselected from hydrogen, methyl, —COR⁵ and a radical of the structure:

where m and n, independently, represent the integers from 0 to 5, whereR¹ is selected from hydrogen, deuterium, hydroxy, protected hydroxy,fluoro, trifluoromethyl, and C₁₋₅-alkyl, which may be straight chain orbranched and, optionally, bear a hydroxy or protected-hydroxysubstituent, and where each of R², R³, and R⁴, independently, isselected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyland C₁₋₅ alkyl, which may be straight-chain or branched, and optionally,bear a hydroxy or protected-hydroxy substituent, and where R¹ and R²,taken together, represent an oxo group, or an alkylidene group, ═CR²R³,or the group —(CH₂)_(p)—, where p is an integer from 2 to 5, and whereR³ and R⁴, taken together, represent an oxo group, or the group—(CH₂)_(q)—, where q is an integer from 2 to 5, and where R⁵ representshydrogen, hydroxy, protected hydroxy, C₁₋₅ alkyl or —OR⁷ where R⁷represents C₁₋₅ alkyl, and wherein any of the CH-groups at positions 20,22, or 23 in the side chain may be replaced by a nitrogen atom, or whereany of the groups —CH(CH₃)—, —CH(R³)—, or —CH(R²)— at positions 20, 22,and 23, respectively, may be replaced by an oxygen or sulfur atom.

The wavy lines, e.g. to the substituents at C-2 and at C-20 indicatethat those substituents may have either the R or S configuration.

Specific important examples of side chains with natural20R-configuration are the structures represented by formulas (a), b),(c), (d) and (e) below. i.e. the side chain as it occurs in25-hydroxyvitamin D₃ (a); vitamin D₃ (b); 25-hydroxvvitamin D₂ (c);vitamin D₂ (d); and the C-24 epimer of 25-hydroxyvitamin D₂ (e):

Specific important examples of side chains with the unnatural 20S (alsoreferred to as the 20-epi) configuration are the structures presented byformulas (f), (g), (h), (i) and (j) below:

The above novel compounds exhibit a desired, and highly advantageous,pattern of biological activity. The synthesized vitamins were tested fortheir ability to bind the porcine intestinal vitamin D receptor. Thepresented results (FIG. 5) indicate that 2-ethylidene-19-norvitamins,possessing methyl group from ethylidene moiety directed toward C-3,i.e., trans in relation to C(6)-C(7) bond (isomers E), are more activethan 1α,25-(OH)₂D₃ in binding to VDR, whereas their counterparts withcis relationship between ethylidene methyl substituent and C(7)-H group(isomers Z) exhibit significantly reduced affinity for the receptor. Thecompetitive binding analysis showed also that 2α-ethyl-19-norvitaminsbind to the receptor better than their isomers with 2β-ethylsubstituents (FIG. 6). In the next assay, the cellular activity of thesynthesized compounds was established by studying their ability toinduce differentiation of human promyelocyte HL-60 cells into monocytes.E isomer of (20S)-2-ethylidene-19-norvitamin D₃ (FIG. 7) and both2α-ethyl-19-norvitamins (FIG. 8) are more potent than 1α,25-(OH)₂D₃ inthis assay, whereas the remaining tested compounds are almost equivalentto the hormone 1. Both E isomers of 2-ethylidene-19-norvitamins, whentested in vivo in rats (Table 1) exhibited very high calcemic activity,the (20S)-compound being especially potent. On the contrary, isomeric Zcompounds are significantly less active. 2-Ethyl-19-norvitamins havesome ability to mobilize calcium from bone but not to the extent of thehormone 1, while being inactive in intestine. The only exception is the2α-ethyl isomer from the 20S-series which shows strong calciummobilization response and marked intestinal activity.

These compounds are thus highly specific in their calcemic activity.Their preferential activity on mobilizing calcium from bone and eitherhigh or normal intestinal calcium transport activity allows the in vivoadministration of these compounds for the treatment of metabolic bonediseases where bone loss is a major concern. Because of theirpreferential calcemic activity on bone, these compounds would bepreferred therapeutic agents for the treatment of diseases where boneformation is desired, such as osteoporosis, especially low bone turnoverosteoporosis, steroid induced osteoporosis, senile osteoporosis orpostmenopausal osteoporosis, as well as osteomalacia and renalosteodystrophy. The treatment may be transdermal, oral or parenteral.The compounds may be present in a composition in an amount from about0.1 μg/gm to about 50 μkg/gm of the composition, and may be administeredin dosages of from about 0.01 μg/day to about 50 μg/day.

The compounds of the invention are also especially suited for treatmentand prophylaxis of human disorders which are characterized by animbalance in the immune system, e.g. in autoimmune diseases, includingmultiple sclerosis, diabetes mellitus, host versus graft reaction,lupus, atherosclerosis, and rejection of transplants; and additionallyfor the treatment of inflammatory diseases, such as inflammatory boweldisease, rheumatoid arthritis and asthma, as well as the improvement ofbone fracture healing and improved bone grafts. Acne, alopeciaespecially chemically induced alopecia (e.g. resulting fromchemotherapy), skin conditions such as dermatitis, eczema, keratosis,dry skin (lack of dermal hydration), undue skin slackness (insufficientskin firmness), insufficient sebum secretion and wrinkles, as well ashypocalcemia, hypoparathyroidism and hypertension are other conditionswhich may be treated with the compounds of the invention.

The above compounds are also characterized by high cell differentiationactivity. Thus, these compounds also provide therapeutic agents for thetreatment of psoriasis, or as an anti-cancer agent, especially againstleukemia, colon cancer,.breast cancer and prostate cancer. The compoundsmay be present in a composition to treat psoriasis, cancer, and/or theabove list of diseases in an amount from about 0.01 μg/gm to about 100μg/gm of the composition, and may be administered topically,transdermally, orally or parenterally in dosages of from about 0.01μg/day to about 100 μg/day.

This invention also provides novel intermediate compounds formed duringthe synthesis of the end products.

This invention also provides a novel synthesis for the production of theend products of structures I and II. Two different synthetic paths weredevised, both based on Lythgoe type Wittig-Horner coupling of the A-ringfragments, the corresponding phosphine oxides prepared from quinic acid,with the protected 25-hydroxy Grundmann's ketone. In the first method,the allylic phosphine oxides were substituted at C-4′ with theethylidene group whereas in the alternative approach the introduction ofethylidene moiety was performed i n the final step of the synthesis, byWittig reaction of the intermediate 2-oxo-vitamin D analog. Theselective catalytic hydrogenation of 2-ethylidene analogs of1α,25-dihydroxy-19-norvitamin D₃ provided the corresponding 2α- and2μ-ethyl compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the general structural formulae for1α,25-dihydroxyvitamin D₃, 1α,25-dihydroxy-2-methylene-19-norvitamin D₃,and 1α,25-dihydroxy-2α-methyl-19-norvitamin D₃, and further illustratesthe general structural formulae for the four2-ethylidene-19-nor-vitamins and the four 2-ethyl-19-nor-vitamins of thepresent invention synthesized and tested herein;

FIG. 2 illustrates the -configurations and preferred conformations ofthe 4′-ethylidene intermediates 16 and 17 used in the synthesisdisclosed herein;

FIG. 3 a illustrates the α- and β-forms of the A-ring chair conformersfor vitamin D compounds in solutions;

FIG. 3 b illustrates that the presence of bulky 2-alkyl substituents,characterized by large conformational free energy A values, shifts theA-ring conformational equilibrium of the synthesized2-ethyl-19-nor-vitamins toward the conformers with the equatorialC(2)-substituents;

FIG. 3 c illustrates that a strong interaction (designated asA^((1,3))-strain) exists between the methyl group from the ethylidenemoiety and equatorial hydroxyls at C-1 or C-3, and results in a strongbias toward conformers with an axial orientation of this hydroxy groupto which the methyl from ethylidene fragment is directed; and

FIG. 4 illustrates the conformational equilibrium in ring A of2-methylene-19-norvitamin 2 (a) and the preferred, energy minimized (PCMODEL 6.0, Serena Software) A-ring conformations of the synthesizedanalogs: 4a,b (b), 5a,b (c), 6a,b (d) and 7a,b (e).

FIG. 5 a is a graph illustrating the relative activity of a2-ethylidene-19-nor-vitamins (isomers E and Z) and1α,25-dihydroxyvitamin D₃ to compete for binding of [³C]-1,25-(OH)₂-D₃to the pig intestinal nuclear vitamin D receptor;

FIG. 5 b is a graph similar to FIG. 5 a except illustrating the relativeactivity of individual compounds 2α and 2β-ethyl-19-nor-vitamins and1α,25-dihydroxyvitamin D₃ to compete for binding of [³H]-1,25-(OH)₂-D₃to the vitamin D pig intestinal nuclear receptor;

FIG. 6 a is a graph illustrating the percent HL-60 cell differentiationas a function of the concentration of the 2-ethylidene-19-nor-vitaminsas compared to 1α,25-dihydroxyvitamin D3; and

FIG. 6 b is a graph illustrating the percent HL-60 cell differentiationas a function of the concentration of the 2α and2β-ethyl-19-nor-vitamins as compared to 1α,25-dihydroxyvitamin D₃.

DETAILED DESCRIPTION OF THE INVENTION

As used in the description and in the claims, the term“hydroxy-protecting group” signifies any group commonly used for thetemporary protection of hydroxy functions, such as for example,alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafterreferred to simply as “silyl” groups), and alkoxyalkyl groups.Alkoxycarbonyl protecting groups are alkyl-O—CO— groupings such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,benzyloxycarbonyl or allyloxycarbonyl. The term “acyl” signifies analkanoyl group of 1 to 6 carbons, in all of its isomeric forms, or acarboxyalkanoyl group of 1 to 6 carbons, such as an oxalyl, malonyl,succinyl, glutaryl group, or an aromatic acyl group such as benzoyl, ora halo, nitro or alkyl substituted benzoyl group. The word “alkyl” asused in the description or the claims, denotes a straight-chain orbranched alkyl radical of 1 to 10 carbons, in all its isomeric forms.Alkoxyalkyl protecting groups are groupings such as methoxymethyl,ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl andtetrahydropyranyl. Preferred silyl-protecting groups are trimethylsilyl,triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl,diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl andanalogous alkylated silyl radicals. The term “aryl” specifies a phenyl-,or an alkyl-, nitro- or halo-substituted phenyl group.

A “protected hydroxy” group is a hydroxy group derivatised or protectedby any of the above groups commonly used for the temporary or permanentprotection of hydroxy functions, e.g. the silyl, alkoxyalkyl, acyl oralkoxycarbonyl groups, as previously defined. The terms “hydroxyalkyl”,“deuteroalkyl” and “fluoroalkyl” refer to an alkyl radical substitutedby one or more hydroxy, deuterium or fluoro groups respectively.

It should be noted in this description that the term “24-homo” refers tothe addition of one methylene group and the term “24-dihomo” refers tothe addition of two methylene groups at the carbon 24 position in theside chain. Likewise, the term “trihomo” refers to the addition of threemethylene groups. Also, the term “26,27-dimethyl” refers to the additionof a methyl group at the carbon 26 and 27 positions so that for exampleR³ and R⁴ are ethyl groups. Likewise, the term “26,27-diethyl” refers tothe addition of an ethyl group at the 26 and 27 positions so that R³ andR⁴ are propyl groups.

In the following lists of compounds, the particular isometric form ofthe ethylidene substituent attached at the carbon 2 position should beadded to the nomenclature. For example, if the methyl group of theethylidene substituent is in its (E) configuration, then the term “2(E)”should be included in each of the named compounds. If the methyl groupof the ethylidene substituent is in its (Z) configuration, then the term“2(Z)” should be included in each of the named compounds. In addition,if the methyl group attached at the carbon 20 position is in its epi orunnatural configuration, the term “20(S)” or “20-epi” should be includedin each of the following named compounds. Also, if the side chaincontains an oxygen atom substituted at any of positions 20, 22 or 23,the term “20-oxa”, “22-oxa” or “23-oxa”, respectively, should be addedto the named compound. The named compounds could also be of the vitaminD₂ or D₄ type if desired.

Specific and preferred examples of the 2-ethylidene-compounds ofstructure I when the side chain is unsaturated are:

2-ethylidene-19-nor-1,25-dihydroxy-22,23-dehydrovitamin D₃;

2-ethylidene-19-nor-24-homo-1,25-dihydroxy-22,23 -dehydrovitamin D₃;

2-ethylidene-19-nor-24-dihomo-1,25-dihydroxy-22,23-dehydrovitamin D₃;

2-ethylidene-19-nor-24-trihomo-1,25-dihydroxy-22,23-dehydrovitamin D₃;

2-ethylidene-19-nor-26,27-dimethyl-24-homo-1,25-dihydroxy-22,23-dehydrovitamin D₃;

2-ethylidene-19-nor-26,27-dimethyl-24-dihomo-1,25-dihydroxy-22,23-dehydrovitaminD₃;

2-ethylidene-19-nor-26,27-dimethyl-24-trihomo-1,25-dihydroxy-22,23-dehydrovitaminD₃;

2-ethylidene-19-nor-26,27-diethyl-24-homo-1,25-dihydroxy-22,23-dehydrovitaminD₃;

2-ethylidene-19-nor-26,27-diethyl-24-dihomo-1,25-dihydroxy-22,23-dehydrovitaminD₃;

2-ethylidene-19-nor-26,27-diethyl-24-trihomo-1,25-dihydroxy-22,23-dehydrovitaminD₃;

2-ethylidene-19-nor-26,27-dipropoyl-24-homo-1,25-dihydroxy-22,23-dehydrovitaminD₃;

2-ethylidene-19-nor-26,27-dipropyl-24-dihomo-1,25-dihydroxy-22,23-dehydrovitaminD₃; and

2-ethylidene-19-nor-26,27-dipropyl-24-trihomo-1,25-dihydroxy-22,23-dehydrovitaminD₃.

With respect to the above unsaturated compounds, it should be noted thatthe double bond located between the 22 and 23 carbon atoms in the sidechain may be in either the (E) or (Z) configuration. Accordingly,depending upon the configuration, the term “22,23(E)” or “22,23(Z)”should be included in each of the above named compounds. Also, it iscommon to designate the double bond located between the 22 and 23 carbonatoms with the designation “Δ²²”. Thus, for example, the first namedcompound above could also be written as2-ethylidene-19-nor-22,23(E)-Δ²²-1,25-(OH)₂D₃ where the double bond isin the (E) configuration. Similarly, if the methyl group attached atcarbon 20 is in the unnatural configuration, this compound could bewritten as 2-ethylidene-19-nor-20(S)-22,23(i)-Δ²²-1,25-(OH)₂D₃.

Specific and preferred examples of the 2-ethylidene-compounds ofstructure I when the side chain is saturated are:

2-ethylidene-19-nor-1,25-dihydroxyvitamin D₃;

2-ethylidene-19-nor-24-homo-1,25-dihydroxyvitamin D₃;

2-ethylidene-19-nor-24-dihomo-1,25-dihydroxyvitamin D₃;

2-ethylidene-19-nor-24-trihomo-1,25-dihydroxyvitamin D₃;

2-ethylidene-19-nor-26,27-dimethyl-24-homo-1,25-dihydroxyvitamin D₃;

2-ethylidene-19-nor-26,27-dimethyl-24-dihomo-1,25-dihydroxyvitamin D₃;

2-ethylidene-19-nor-26,27-dimethyl-24-trihomo-1,25-dihydroxyvitamin D₃;

2-ethylidene-19-nor-26,27-diethyl-24-homo-1,25-dihydroxyvitamin D₃;

2-ethylidene-19-nor-26,27-diethyl-24-dihomo-1,25-dihydroxyvitamin D₃;

2-ethylidene-19-nor-26,27-diethyl-24-trihomo-1,25-dihydroxyvitamin D₃;

2-ethylidene-19-nor-26,27-dipropyl-24-homo-1,25-dihydroxyvitamin D₃;

2-ethylidene-19-nor-26,27-dipropyl-24-dihomo-1,25-dihydroxyvitamin D₃;and

2-ethylidene-19-nor-26,27-dipropyl-24-trihomo-1,25-dihydroxyvitamin D₃.

As noted previously, the above saturated side chain compounds shouldhave the appropriate 2(E) or 2(Z) configuration and/or carbon 20configuration added to the nomenclature. For example, particularlypreferred compounds are:

19-nor-2(E)-ethylidene-1α,25-dihydroxyvitamin D₃;

19-nor-2(Z)-ethylidene-1α,25-dihydroxyvitamin D₃;

19-nor-2(E)-ethylidene-20(S)-1α,25-dihydroxyvitamin D₃; and

19-nor-2(Z)-ethylidene-20(S)-1α,25-dihydroxyvitamin D₃.

In the following lists of compounds, the particular isometric form ofthe ethyl substituent attached at the carbon 2 position should be addedto the nomenclature. For example, if the ethyl group is in the alphaconfiguration, the term “2α-methyl” should be included in each of thenamed compounds. If the ethyl group is in the beta configuration, theterm “2β-ethyl” should be included in each of the named compounds. Inaddition, if the methyl group attached at the carbon 20 position is inits epi or unnatural configuration, the term “20(S)” or “20-epi” shouldbe included in each of the following named compounds. Also, if the sidechain contains an oxygen atom substituted at any of positions 20, 22 or23, the term “20-oxa,” “22-oxa” or “23-oxa,” respectively, should beadded to the named compound. The named compounds could also be of thevitamin D₂ or D₄ type if desired.

Specific and preferred examples of the 2-ethyl-compounds of structure IIwhen the side chain is unsaturated are:

2-ethyl-19-nor-1,25-dihydroxy-22,23-dehydrovitamin D₃;

2-ethyl-19-nor-24-homo-1,25-dihydroxy-22,23-dehydrovitamin D₃;

2-ethyl-19-nor-24-dihomo-1,25-dihydroxy-22,23-dehydrovitamin D₃;

2-ethyl-19-nor-24-trihomo-1,25-dihydroxy-22,23-dehydrovitamin D₃;

2-ethyl-19-nor-26,27-dimethyl-24-homo-1,25-dihydroxy-22,23-dehydrovitaminD₃;

2-ethyl-19-nor-26,27-dimethyl-24-dihomo-1,25-dihydroxy-22,23-dehydrovitaminD₃;

2-ethyl-19-nor-26,27-dimethyl-24-trihomo-1,25-dihydroxy-22,23-dehydrovitaminD₃;

2-ethyl-19-nor-26,27-diethyl-24-homo-1,25-dihydroxy-22,23-dehydrovitaminD₃;

2-ethyl-19-nor-26,27-diethyl-24-dihomo-1,25-dihydroxy-22,23-dehydrovitaminD₃;

2-ethyl-19-nor-26,27-diethyl-24-trihomo-1,25-dihydroxy-22,23-dehydrovitaminD₃;

2-ethyl-19-nor-26,27-dipropoyl-24-homo-1,25-dihydroxy-22,23-dehydrovitaminD₃;

2-ethyl-19-nor-26,27-dipropyl-24-dihomo-1,25-dihydroxy-22,23-dehydrovitaminD₃; and

2-ethyl-19-nor-26,27-dipropyl-24-trihomo-1,25-dihydroxy-22,23-dehydrovitaminD₃.

With respect to the above unsaturated compounds, it should be noted thatthe double bond located between the 22 and 23 carbon atoms in the sidechain may be in either the (E) or (Z) configuration. Accordingly,depending upon the configuration, the term “22,23(E)” or “22,23(Z)”should be included in each of the above named compounds. Also, it iscommon to designate the double bond located between the 22 and 23 carbonatoms with the designation “Δ²²”. Thus, for example, the first namedcompound above could also be written as2-ethyl-19-nor-22,23(E)-Δ²²-1,25-(OH)₂D₃ where the double bond is in the(E) configuration. Similarly, if the methyl group attached at carbon 20is in the unnatural configuration, this compound could be written as2-ethyl-19-nor-20(S)-22,23(E)-Δ²²-1,25-(OH)₂D₃.

Specific and preferred examples of the 2-ethyl-compounds of structure IIwhen the side chain is saturated are:

2-ethyl-19-nor-1,25-dihydroxyvitamin D₃;

2-ethyl-19-nor-24-homo-1,25-dihydroxyvitamin D₃;

2-ethyl-19-nor-24-dihomo-1,25-dihydroxyvitamin D₃;

2-ethyl-19-nor-24-trihomo-1,25-dihydroxyvitamin D₃;

2-ethyl-19-nor-26,27-dimethyl-24-homo-1,25-dihydroxyvitamin D₃;

2-ethyl-19-nor-26,27-dimethyl-24-dihomo-1,25-dihydroxyvitamin D₃;

2-ethyl-19-nor-26,27-dimethyl-24-trihomo-1,25-dihydroxyvitamin D₃;

2-ethyl-19-nor-26,27-diethyl-24-homo-1,25-dihydroxyvitamin D₃;

2-ethyl-19-nor-26,27-diethyl-24-dihomo-1,25-dihydroxyvitamin D₃;

2-ethyl-19-nor-26,27-diethyl-24-trihomo-1,25-dihydroxyvitamin D₃;

2-ethyl-19-nor-26,27-dipropyl-24-homo-1,25-dihydroxyvitamin D₃;

2-ethyl-19-nor-26,27-dipropyl-24-dihomo-1,25-dihydroxyvitamin D₃; and

2-ethyl-19-nor-26,27-dipropyl-24-trihomo-1,25-dihydroxyvitamin D₃.

As noted previously, the above saturated side chain compounds shouldhave the appropriate 2α- or 2β-configuration and/or carbon 20configuration added to the nomenclature. For example, particularlypreferred compounds are:

19-nor-2α-ethyl-1α,25-dihydroxyvitamin D₃;

19-nor-2β-ethyl-1α,25-dihydroxyvitamin D₃;

19-nor-20(S)-2α-ethyl-1α,25-dihydroxyvitamin D₃; and

19-nor-20(S)-2β-ethyl-1α,25-dihydroxyvitamin D₃.

The preparation of 2-ethylidene-19-nor-vitamin D compounds, and the2-ethyl-19-nor-vitamin D compounds, having the basic structure I and IIcan be accomplished by a common general method, i.e. the condensation ofa bicyclic Windaus-Grundmann type ketone III with the allylic phosphineoxide IVa or IVb to the corresponding 2-ethylidene-19-nor-vitamin Danalogs Va or Vb, respectively followed by a selective reduction of theethylidene group at C-2 to the corresponding 2-ethyl compounds.

In the structures III, IV, and V groups Y₁ and Y₂ and R represent groupsdefined above; Y₁ and Y₂ are preferably hydroxy-protecting groups, itbeing also understood that any functionalities in R that might besensitive, or that interfere with the condensation reaction, be suitableprotected as is well-known in the art. The process shown aboverepresents an application of the convergent synthesis concept, which hasbeen applied effectively for the preparation of vitamin D compounds[e.g. Lythgoe et al., J. Chem. Soc. Perkin Trans. I, 590 (1978);Lythgoe, Chem. Soc. Rev. 9, 449 (1983); Toh et al., J. Org. Chem. 48,1414 (1983); Baggiolini et al., J. Org. Chem. 51, 3098 (1986); Sardinaet al., J. Org. Chem. 51, 1264 (1986); J. Org. Chem. 51 , 1269 (1986);DeLuca et al., U.S. Pat. No. 5,086,191; DeLuca et al., U.S. Pat. No.5,536,713].

Hydrindanones of the general structure m are known, or can be preparedby known methods. Specific important examples of such known bicyclicketones are the structures with the side chains (a), (b), (c) and (d)described above, i.e. 25-hydroxy Grundmann's ketone (f) [Baggiolini etal., J. Org. Chem, 51, 3098 (1986)]; Grundmann's ketone (g) [Inhoffen etal., Chem. Ber. 90, 664 (1957)]; 25-hydroxy Windaus ketone (h)[Baggiolini et al., J. Org. Chem., 51, 3098 (1986)] and Windaus ketone(i) [Windaus et al., Ann., 524, 297 (1936)]:

For the preparation of the required phosphine oxides of generalstructure IV, a new synthetic route has been developed starting frommethyl quinicate derivative 9, easily obtained from commercial(1R,3R,4S,5R)-(−)-quinic acid 8 as described by Perlman et al.,Tetrahedron Lett. 32, 7663 (1991) and DeLuca et al., U.S. Pat. No.5,086,191. The overall process of transformation of the starting methylester 9 into the desired A-ring synthons, is summarized by the Scheme I.Reduction of the ester 9 with diisobutylaluminum hydride (DIBALH) orother suitable reducing agent (e.g. lithium aluminum hydride) providedthe diol 10 which was subsequently oxidized by sodium periodate to thecyclohexanone ketone derivative 11. Then, the secondary 4-hydroxyl groupof 11 was oxidized with RuO₄ (a catalytic method with RuCl₃ and NaIO₄ asco-oxidant). Use of such a strong oxidant was necessary for an effectiveoxidation process of this very hindered hydroxyl. However, other morecommonly used oxidants can also be applied (e.g. pyridinium dichromate),although the reactions usually require much longer time for completion.The next step of the process comprises the Peterson reaction of theketone 12 with methyl(trimethylsilyl)acetate to form ester 13.

Referring now to Scheme 2, the next step of the synthesis comprises theWittig reaction of the sterically hindered 4-keto compound 13 with ylideprepared from ethyltriphenylphosphonium bromide and n-butyllithiumleading to ethylidene compounds 14 and 15. Ethylidene compounds 14 and15 in turn were treated with diisobutylaluminum hydride and the formedalcohols 16 and 17 were in turn transformed to the desired A-ringphosphine oxides 18 and 19. Conversion of 16 and 17, to 18 and 19,respectively involved 3 steps, namely, in situ tosylation withn-butyllithium and p-toluenesulfonyl chloride, followed by reaction withdiphenylphosphine lithium salt and oxidation with hydrogen peroxide.

Several 2-ethylidene-19-nor-vitamin D compounds of the general structureV may be synthesized using the A-ring synthons 18 and 19 and theappropriate Windaus-Grundmann ketone III having the desired side chainstructure. Thus, for example, Scheme 3 illustrates that Wittig-Hornercoupling of the phosphinoxy 18 with the protected 25-hydroxy Grundmann'sketone 20 prepared according to published procedure [Sicinski et al., J.Med. Chem. 37, 3730 (1994)] gave the expected protected vitamin compound21. This, after deprotection afforded1α,25-dihydroxy-2(E)-ethylidene-19-nor-vitamin D₃ (4a). Similarly,Scheme 3 illustrates the synthesis of1α,25-dihydroxy-2(Z)-ethylidene-19-nor-vitamin D₃(5a) from phosphinoxy19 and Grundmann's ketone 20.

Referring now to Scheme 6, the final step of the process was theselective homogeneous catalytic hydrogenation of the ethylidene unit atcarbon 2 in the vitamins 4a and 5a performed efficiently in the presenceof tris(triphenylphosphine)rhodium(I) chloride [Wilkinson's catalyst,(Ph₃P)₃RhCl]. Such reduction conditions allowed to reduce only C(2)═CH₂unit leaving C(5)—C(8) butadiene moiety unaffected. The isolatedmaterial is an epimeric mixture (ca. 1:1) of 2-ethyl-19-nor-vitamins 6aand 7a differing in configuration at C-2. The mixture can be usedwithout separation or, if desired, the individual 2α- and 2β-isomers canbe separated by an efficient HPLC system.

The C-20 epimerization may be accomplished by the analogous coupling ofthe phosphine oxides 18 and 19 with protected 20(S)-25-hydroxyGrundmann's ketone 26 (Scheme 5) which after hydrolysis of thehydroxy-protecting groups gave20(S)-1α,25-dihydroxy-2-ethylidene-19-nor-vitamin D₃ compounds 4b and5b. Hydrogenation of 4b and 5b provided the expected mixture of the2-ethyl-19-nor-vitamin D analogs 6b and 7b.

As noted above, other 2-ethylidene and 2-ethyl-19-nor-vitamin D analogsmay be synthesized by the method disclosed herein. For example,1α-hydroxy-2-ethylidene-19-nor-vitamin D₃ can be obtained by providingthe Grundmann's ketone (g). Subsequent reduction of the A-ringethylidene group in the formed compound can also give the correspondingepimeric mixture of 1α-hydroxy-2-ethyl-19-nor-vitamin D₃ compounds.

A number of oxa-analogs of vitamin D₃ and their synthesis are alsoknown. For example, 20-oxa analogs are described in N. Kubodera at al,Chem. Pharm. Bull., 34, 2286 (1986), and Abe et al, FEBS Lett. 222,58,1987. Several 22-oxa analogs are described in E. Murayama et al, Chem.Pharm. Bull., 34, 4410 (1986), Abe et al, FEBS Lett., 226, 58 (1987),PCT International Application No. WO 90/09991 and European PatentApplication, publication number 184 112, and a 23-oxa analog isdescribed in European Patent Application, publication number 78704, aswell as U.S. Pat. No. 4,772,433.

This invention is described by the following illustrative examples. Inthese examples specific products identified by Arabic numerals (e.g. 1,2, 3, etc) refer to the specific structures so identified in thepreceding description and in the Schemes.

EXAMPLE 1 CHEMISTRY

The strategy of the synthesis of 2-substituted 19-norvitamins was basedon Lythgoe-type Wittig-Horner coupling. Since the corresponding C,D-ringketones were available, attention was focused on the synthesis of thephosphine oxide A-ring synthons (Scheme 1 and 2). Configurations of theethylidene unit at C′-4 in the isomeric compounds 16, 17 (FIG. 2) and17, 18, as well as their preferred conformations, were determined byanalysis of ¹H NMR spectra, NOE measurements and spin decouplingexperiments.

The Wittig-Homer reaction of the conjugate base of 20 with the protected25-hydroxy Grundmann's ketone 20 produced 19-norvitamin D compound 21 ina very high yield, i.e. 91% (Scheme 3), but-the yield of an analogouscoupling of the isomeric phosphine oxide 19 was very low, i.e. 13%. Theobtained condensation products 21 and 22, following deprotection, gave2-ethylidene-19-norvitamins 4a and 5a. Considering the low yield of theWittig reaction of the cyclohexanone 13, leading to ethylidene compounds14 and 15 (Scheme 2), an alternative synthetic approach was sought.

Thus, the carbonyl group in 13 was protected as O-trimethylsilylhemimethylthioketal and the corresponding phosphine oxides 25 wereefficiently synthesized (Scheme 4). Coupling of their anions with thehydrindanone 26 (Scheme 5) afforded the protected 19-norvitamin Dcompound 27 in a high yield. This, after deprotection of 2-oxo group,Wittig reaction and subsequent hydrolysis was converted to(20S)-2-ethylidene-19-norvitamins 4b and 5b. The selective catalytichydrogenation of 2-ethylidene analogs 4a, b and 5a, b (Scheme 6)provided the corresponding 2-ethyl-19-norvitamins 6a, b and 7a, b, whichwere easily separated by HPLC.

Stereochemistry at C-2 in the synthesized vitamin D compounds wastentatively assigned on the basis of conformational analysis, molecularmodeling studies, and 500 MHz ¹H NMR spectroscopy.

EXAMPLE 2 CONFORMATIONAL ANALYSIS

It has been established that vitamin D compounds in solutions exist as amixture of two rapidly equilibrating A-ring chair conformers abbreviatedas α- and β-forms (FIG. 3 a). Presence of bulky 2-alkyl substituents,characterized by large conformational free energy A values (FIG. 3 b),shifts the A-ring conformational equilibrium of the synthesized2-ethyl-19-norvitamins toward the conformers with the equatorialC(2)-substituents. In the obtained 2-ethylidene-19-norvitamin Dcompounds, an additional strong interaction (designated asA^((1,3))-strain, FIG. 3 c) is involved, existing between the methylgroup from the ethylidene moiety and equatorial hydroxyls at C-1 or C-3.It results in the strong bias toward conformers with an axialorientation of this hydroxy group to which the methyl from ethylidenefragment is directed.

Conformational equilibrium in ring A of 2-methylene-19-norvitamin 2 (a)and-the preferred, energy minimized (PC MODEL 6.0, Serena Software)A-ring conformations of the synthesized analogs: 4a, b (b), 5a, b (c),6a, b :(d) and 7a, b (e) are shown in FIG. 4. The steric energydifferences between the preferred conformers and their partners with theinverted chair forms (calculated for model compounds lacking side chain)are given. The corresponding percentage populations (in parentheses) ofconformers are given for room temperature (25° C.).

EXAMPLE 3 BIOLOGICAL EVALUATION

The synthesized vitamins were tested for their ability to bind theporcine intestinal vitamin D receptor. The presented results (FIG. 5 a)indicate that 2-ethylidene-19-norvitamins, possessing methyl group fromethylidene moiety directed toward C-3, i.e. trans in relation toC(6)—C(7) bond (isomers E), are more active than 1α,25-(OH)₂D₃ inbinding to VDR, whereas their counterparts with cis relationship betweenethylidene methyl substituent and C(7)-H group (isomers Z) exhibitsignificantly reduced affinity for the receptor. The competitive bindinganalysis showed also that 2α-ethyl-19-norvitamins bind the receptorbetter than their isomers with 2β-ethyl substituents (FIG. 5 b). In thenext assay, the cellular activity of the synthesized compounds wasestablished by studying their ability to induce differentiation of humanpromyelocyte HL-60 cells into monocytes. E isomer of(20S)-2-ethylidene-19-norvitamin D₃ (FIG. 6 a) and both2α-ethyl-19-norvitamins (FIG. 6 b) are more potent than 1α,25-(OH)₂D₃ inthis assay, whereas the remaining tested compounds are almost equivalentto the hormone.

Both E isomers of 2-ethylidene-19-norvitamins, when tested in vivo inrats (Table 1) exhibited very high calcemic activity, the (20S)-compoundbeing especially potent. On the contrary, isomeric Z compounds aresignificantly less active. 2-ethyl-19-norvitamins have some ability tomobilize calcium from bone but not to the extent of the hormone 1, whilebeing inactive in intestine. The only exception is 2α-ethyl isomer from20S-series that shows strong calcium mobilization response and markedintestinal activity. TABLE 1 Support of Intestinal Calcium Transport andBone Calcium Mobilization By 2-Substituted Analogs of1α,25-Dihydroxy-19-norvitamin D₃ In Vitamin D-Deficient Rats on aLow-Calcium Diet^(a) compd. amount Ca transport S/M Serum Ca compoundno. (pmol) (mean ± SEM) (mean ± SEM) none (control) 0 3.0 ± 0.7 4.3 ±0.1 1α,25-(OH)₂D₃ 1 130 5.5 ± 0.5 5.1 ± 0.3 260 5.9 ± 0.4 5.8 ± 0.32-ethylidene-19-nor- 4a 65 5.0 ± 0.4 4.5 ± 0.1 1α,25-(OH)₂D₃ (E-isomer)130 6.8 ± 0.4 5.2 ± 0.2 2-ethylidene-19-nor-1α,25- 5a 65 4.4 ± 0.4 4.4 ±0.2 (OH)₂D₃ (Z-isomer) 130 5.7 ± 0.9 4.2 ± 0.0 none (control) 0 4.4 ±0.2 4.1 ± 0.2 1α,25-(OH)₂D₃ 1 130 4.9 ± 0.7 5.2 ± 0.2 260 6.0 ± 0.9 6.4± 0.4 2-ethylidene-19-nor-(20S)- 4b 65 9.0 ± 0.3 8.2 ± 0.3 1α,25-(OH)₂D₃(E-isomer) 130 5.8 ± 0.8 12.1 ± 0.6  2-ethylidene-19-nor-(20S)-1α,25- 5b65 4.3 ± 0.7 4.0 ± 0.3 (OH)₂D₃ (Z-isomer) 130 3.8 ± 0.3 4.0 ± 0.1 none(control) 0 3.8 ± 0.4 3.9 ± 0.1 1α,25-(OH)₂D₃ 1 260 6.5 ± 0.9 5.8 ± 0.12α-ethyl-19-nor- 6a 260 4.0 ± 0.4 5.1 ± 0.1 1α,25-(OH)₂D₃2β-ethyl-19-nor- 7a 260 3.7 ± 0.3 5.0 ± 0.1 1α,25-(OH)₂D₃2α-ethyl-19-nor- 6b 260 5.0 ± 0.4 7.0 ± 0.1 (20S)-1α,25-(OH)₂D₃2β-ethyl-19-nor- 7b 260 4.1 ± 0.3 5.6 ± 0.1 (20S)-1α,25-(OH)₂D₃^(a)Weanling male rats were maintained on a 0.47% Ca diet for one weekand then switched to a low-calcium diet containing 0.02% Ca for anadditional three weeks. During the last week, they were dosed daily withthe appropriate vitamin D compound for seven consecutive days. All doseswere administered intraperitoneally in 0.1 mL propylene glycol/ethanol(95:5). Controls received the vehicle. Determinations were made 24 hoursafter the last dose. There were at least six rats per group.

For treatment purposes, the novel compounds of this invention defined byformula I and/or II may be formulated for pharmaceutical applications asa solution in innocuous solvents, or as an emulsion, suspension ordispersion in suitable solvents or carriers, or as pills, tablets orcapsules, together with solid carriers, according to conventionalmethods known in the art. Any such formulations may also contain otherpharmaceutically-acceptable and non-toxic excipients such asstabilizers, anti-oxidants, binders, coloring agents or emulsifying ortaste-modifying agents.

The compounds may be administered orally, topically, parenterally,sublingually, intranasally, or transdermally. The compounds areadvantageously administered by injection or by intravenous infusion orsuitable sterile solutions, or in the form of liquid or solid doses viathe alimentary canal, or in the form of creams, ointments, patches, orsimilar vehicles suitable for transdermal applications. Doses of fromabout 0.01 μg to about 100 μg per day,.preferably from 0.1 μg to 50 μgper day of the compounds are appropriate for treatment purposes, suchdoses being adjusted according to the disease to be treated, itsseverity and the response of the subject as is well understood in theart. Since the new compounds exhibit specificity of action, each may besuitably administered alone, or together with graded doses of anotheractive vitamin D compound—e.g. 1α-hydroxyvitamin D₂ or D₃, or1α,25-dihydroxyvitamin D₃—in situations where different degrees of bonemineral mobilization and calcium transport stimulation is found to beadvantageous.

Compositions for use in the above-mentioned treatment of psoriasis andother malignancies comprise an effective amount of one or more2-substituted-19-nor-vitamin D compound as defined by the above formulaI and/or II as the active ingredient, and a suitable carrier. Aneffective amount of such compounds for use in accordance with thisinvention is from about 0.01 μg to about 100 μg per gm of composition,and may be administered topically, transdermally, orally, sublingually,intranasally, or parenterally in dosages of from about 0.1 μg/day toabout 100 μg/day.

The compounds may be formulated as creams, lotions, ointments, topicalpatches, pills, capsules or tablets, or in liquid form as solutions,emulsions, dispersions, or suspensions in pharmaceutically innocuous andacceptable solvent or oils, and such preparations may contain inaddition other pharmaceutically innocuous or beneficial components, suchas stabilizers, antioxidants, emulsifiers, coloring agents, binders ortaste-modifying agents.

The compounds are advantageously administered in amounts sufficient toeffect the differentiation of promyelocytes to normal macrophages.Dosages as described above are suitable, it being understood that theamounts given are to be adjusted in accordance with the severity of thedisease, and the condition and response of the subject as is wellunderstood in the art.

The formulations of the present invention comprise an active ingredientin association with a pharmaceutically acceptable carrier therefore andoptionally other therapeutic ingredients. The carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulations and not deleterious to the recipient thereof.

Formulations of the present invention suitable for oral administrationmay be in the form of discrete units as capsules, sachets, tablets orlozenges, each containing a predetermined amount of the activeingredient; in the form of a powder or granules; in the form of asolution or a suspension in an aqueous liquid or non-aqueous liquid; orin the form of an oil-in-water emulsion or a water-in-oil emulsion.

Formulations for rectal administration may be in the form of asuppository incorporating the active ingredient and carrier such ascocoa butter, or in the form of an enema.

Formulations suitable for parenteral administration convenientlycomprise a sterile oily or aqueous preparation of the active ingredientwhich is preferably isotonic with the blood of the recipient.

Formulations suitable for topical administration include liquid orsemi-liquid preparations such as liniments, lotions, applicants,oil-in-water or water-in-oil emulsions such as creams, ointments orpastes; or solutions or suspensions such as drops; or as sprays.

For asthma treatment, inhalation of powder, self-propelling or sprayformulations, dispensed with a spray can, a nebulizer or an atomizer canbe used. The formulations, when dispensed, preferably have a particlesize in the range of 10 to 100μ.

The formulations may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.By the term “dosage unit” is meant a unitary, i.e. a single dose whichis capable of being administered to a patient as a physically andchemically stable unit dose comprising either the active ingredient assuch or a mixture of it with solid or liquid pharmaceutical diluents orcarriers.

In its broadest application, the present invention relates to any19-nor-analog of vitamin D which have the vitamin D nucleus. By vitaminD nucleus, it is meant a central part consisting of a substituted chainof five carbon atoms which correspond to positions 8, 14, 13, 17 and 20of vitamin D, and at the ends of which are connected at position 20 astructural moiety representing any of the typical side chains known forvitamin D type compounds (such as R as previously defined herein), andat position 8 the 5,7-diene moiety connected to the A-ring of an active1α-hydroxy vitamin D analog (as illustrated by formula I herein). Thus,various known modifications to the six-membered C-ring and thefive-membered D-ring typically present in vitamin D, such as the lack ofone or the other or both, are also embraced by the present invention.

1-75. (canceled)
 76. A method of treating psoriasis comprisingadministering to a patient with psoriasis an effective amount of acompound selected from the group consisting of:19-nor-2α-ethyl-1α,25-dihydroxyvitamin D₃,19-nor-2β-ethyl-1α,25-dihydroxyvitamin D₃,19-nor-20(S)-2α-ethyl-1α,25-dihydroxyvitamin D₃,19-nor-20(S)-2β-ethyl-1α,25-dihydroxyvitamin D₃,19-nor-2(E)-ethylidene-1α,25-dihydroxyvitamin D₃,19-nor-2(Z)-ethylidene-1α,25-dihydroxyvitamin D₃,19-nor-2(E)-ethylidene-20(S)-1α,25-dihydroxyvitamin D₃, and19-nor-2(Z)-ethylidene-20(S)-1α,25-dihydroxyvitamin D₃
 77. The method ofclaim 76 wherein said effective amount comprises about 0.1 μg/day toabout 100 μg/day of said compound
 78. The method of claim 76 wherein thecompound is 19-nor-2α-ethyl-1α,25-dihydroxyvitamin D₃.
 79. The method ofclaim 76 wherein the compound is 19-nor-2β-ethyl-1α,25-dihydroxyvitaminD₃.
 80. The method of claim 76 wherein the compound is19-nor-20(S)-2α-ethyl-1α,25-dihydroxyvitamin D₃.
 81. The method of claim76 wherein the compound is 19-nor-20(S)-2β-ethyl-1α,25-dihydroxyvitaminD₃.
 82. The method of claim 76 wherein the compound is19-nor-2(E)-ethylidene-1α,25-dihydroxyvitamin D₃.
 83. The method ofclaim 76 wherein the compound is19-nor-2(Z)-ethylidene-1α,25-dihydroxyvitamin D₃.
 84. The method ofclaim 76 wherein the compound is 19-nor-2(E)-ethylidene-20(S)-1α,25-dihydroxyvitamin D₃.
 85. The method of claim 76 wherein the compound is19-nor-2(Z)-ethylidene-20(S)-1α,25-dihydroxyvitamin D₃. 86-116.(canceled)
 117. The method of claim 76 wherein the compound isadministered orally.
 118. The method of claim 76 wherein the compound isadministered parenterally.
 119. The method of claim 76 wherein thecompound is administered transdermally.
 120. The method of claim 76wherein the compound is administered topically.
 121. The method of claim76 wherein the compound is administered in a dosage of from about 0.01μg to about 100 μg per day.
 122. The method of claim 76 wherein thecompound is administered in a dosage of from about 0.1 μg to about 50 μgper day.